Toll-like receptor alterations in myelodysplastic syndrome.

Recent studies have implicated the innate immunity system in the pathogenesis of myelodysplastic syndromes (MDS). Toll-like receptor (TLR) genes encode key innate immunity signal initiators. We recently identified multiple genes, known to be regulated by TLRs, to be overexpressed in MDS bone marrow (BM) CD34+ cells, and hypothesized that TLR signaling is abnormally activated in MDS. We analyzed a large cohort of MDS cases and identified TLR1, TLR2 and TLR6 to be significantly overexpressed in MDS BM CD34+ cells. Deep sequencing followed by Sanger resequencing of TLR1, TLR2, TLR4 and TLR6 genes uncovered a recurrent genetic variant, TLR2-F217S, in 11% of 149 patients. Functionally, TLR2-F217S results in enhanced activation of downstream signaling including NF-κB activity after TLR2 agonist treatment. In cultured primary BM CD34+ cells of normal donors, TLR2 agonists induced histone demethylase JMJD3 and interleukin-8 gene expression. Inhibition of TLR2 in BM CD34+ cells from patients with lower-risk MDS using short hairpin RNA resulted in increased erythroid colony formation. Finally, RNA expression levels of TLR2 and TLR6, as well as presence of TLR2-F217S, are associated with distinct prognosis and clinical characteristics. These findings indicate that TLR2-centered signaling is deregulated in MDS, and that its targeting may have potential therapeutic benefit in MDS.

Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells.

The molecular bases of myelodysplastic syndromes (MDS) are not fully understood. Trimethylated histone 3 lysine 4 (H3K4me3) is present in promoters of actively transcribed genes and has been shown to be involved in hematopoietic differentiation. We performed a genome-wide H3K4me3 CHIP-Seq (chromatin immunoprecipitation coupled with whole genome sequencing) analysis of primary MDS bone marrow (BM) CD34+ cells. This resulted in the identification of 36 genes marked by distinct higher levels of promoter H3K4me3 in MDS. A majority of these genes are involved in nuclear factor (NF)-κB activation and innate immunity signaling. We then analyzed expression of histone demethylases and observed significant overexpression of the JmjC-domain histone demethylase JMJD3 (KDM6b) in MDS CD34+ cells. Furthermore, we demonstrate that JMJD3 has a positive effect on transcription of multiple CHIP-Seq identified genes involved in NF-κB activation. Inhibition of JMJD3 using shRNA in primary BM MDS CD34+ cells resulted in an increased number of erythroid colonies in samples isolated from patients with lower-risk MDS. Taken together, these data indicate the deregulation of H3K4me3 and associated abnormal activation of innate immunity signals have a role in the pathogenesis of MDS and that targeting these signals may have potential therapeutic value in MDS.

[Very late malignant complications of Hodgkin lymphoma]. / Complications malignes très tardives d'un lymphome de Hodgkin.

Overall survival of patients with Hodgkin lymphoma has dramatically increased in recent years, with an increased rate of malignant complications. We report here a 54-year-old man who presented with concomitant relapse of classical Hodgkin's lymphoma and lung adenocarcinoma 20 years after initial treatment with chemotherapy and mantle radiotherapy. Pathogenic mechanisms of these malignant complications are discussed. A prolonged follow-up of patients with Hodgkin's lymphoma is required.

Complete recovery from Cryptosporidium parvum infection with gastroenteritis and sclerosing cholangitis after successful bone marrow transplantation in two brothers with X-linked hyper-IgM syndrome.

We describe two brothers who suffered from hyper-IgM syndrome (HIGM1) with similar clinical features: recurrent infections, especially cryptosporidium gastroenteritis with cholangitis. Their activated T cells did not express CD40L. Nucleotide sequencing revealed a mutation in both boys with respect to intron 4 and exon 5 boundaries of the CD40L gene in Xq26. They underwent successful bone marrow transplantation (BMT) from HLA-geno-identical siblings. The Cryptosporidium infection and cholangitis resolved thereafter. At 6 months after BMT, expression of CD40L on activated T lymphocytes was normal. After 1 year, both boys are well, and immune reconstitution has improved. Based on these two successful experiences, BMT with a genoidentical sibling seems a reasonable therapeutic approach for HIGM1, if Cryptosporidium infection occurs.

[Acute myeloblastic leukemia without maturation (AML-M1) with basophilic elements and associated with translocation t(6;9)]. / Leucémie aiguë myéloblastique sans maturation (LAM1) avec éléments basophiles associée à la translocation t(6;9).

The clinical, hematological, and cytogenetic data from a 4 year-old child with acute myeloid (AML-M1) and basophilia is reported. Interestingly, cytogenetic investigations revealed the presence of the translocation t(6;9) (p23;q34). This abnormality is rare and associated with myelodysplastic syndromes or with subtypes of acute myeloid leukemia (M1, M2, M4, M7), usually with preceding or underlying myelodysplasia. The prognosis is poor, without response to chemotherapy regimen alone. Allogeneic bone marrow transplantation appears likely to be a more appropriate treatment.

[Granulocyte sarcoma of the pancreas without extra-pancreatic location]. / Sarcome granulocytaire du pancréas sans autre localisation extra-pancréatique.

INTRODUCTION: Granulocyte sarcoma (GS), also known as chloroma, is a localized malignant tumor composed of myeloid cells, the diagnosis of which is difficult. The pancreatic location and recurrence, aside from any context of malignant hemopathy, are exceptional. OBSERVATION: A 31-year-old woman developed an isolated and recurrent granulocyte sarcoma of the pancreas, without any context of a malignant hemopathy. The diagnosis retained on extemporaneous examination was an adenocarcinoma of the pancreas, because of the non-specific necrotic nature of the tumor. The immuno-histochemical exploration corrected the diagnosis. Despite local surgery, an isolated tumor recurred 6 months later. This relapse was treated with radiotherapy followed by heavy chemotherapy, identical to that applied in acute myeloblastic leukemia (AML). Ten months later, remission was stable and complete. COMMENTS: Isolated granulocyte sarcomas located in the pancreas are exceptional and have often led to initial erroneous diagnosis. Immuno-histochemical methods are essential in order to obtain correct diagnosis. Despite the localized nature of the tumor, intensive AML-type chemotherapy is necessary.